Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis.

BACKGROUND: The tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive. METHODS: We used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo. RESULTS: TRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15. CONCLUSIONS: TRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.

Levels of neuronal pentraxin 2 in plasma is associated with cognitive function in patients with schizophrenia.

RATIONALE: The precise diagnosis and treatment of cognitive impairment remains a major challenge in the field of schizophrenia (SCZ) research. Synaptic dysfunction and loss are thought to be closely related to the occurrence and development of SCZ and may be involved in cognitive dysfunction. OBJECTIVES: The purpose of this study was to investigate whether neuronal pentraxins (NPTXs) plays a role in the etiology of SCZ and provide evidence of its possible therapeutic value a new target for drug development. METHODS: We recruited 275 participants, of whom 148 were SCZ from psychiatric hospital and 127 healthy control (HC) subjects from communities. Plasma concentrations of NPTXs were measured in HC and SCZ at baseline and after 8 weeks of antipsychotic treatment. The MATRICS Cognitive Consensus Battery was used to evaluate cognitive function. Furthermore, the brain is parcellated into 246 subregions using the Brainnetome atlas, and we extracted regional white matter volumes from magnetic resonance images of the SCZ groups. RESULTS: Plasma NPTX2 levels were significantly lower in SCZ compared with HC subjects, but were significantly raised in SCZ after 8 weeks of antipsychotic treatment compared to baseline. In addition, baseline plasma NPTX2 levels were positively correlated with cognitive performance. CONCLUSIONS: These findings indicate that NPTX2 may reveal novel aspects of disease etiology and act as a promising target for new drug development.

Identification and validation of STAT4 as a prognostic biomarker in acute myeloid leukemia.

Acute myelogenous leukemia (AML) is a common malignancy and is supposed to have the ability to escape host immune surveillance. The present study aimed to identify key genes in AML that may affect tumor immunity and to provide prognosis biomarkers of AML. The Cancer Genome Atlas (TCGA) dataset was screened for transcription factors (TFs) involved in immunity and influencing survival, combining Gene Expression Omnibus (GEO) data to validate the impact on patient survival. A prognostic signature was established using four transcription factors, and these genes play an important role in the immune system, with higher regulatory T cell (Treg) scores in high-risk patients compared with the low-risk group. Analysis of individual genes showed that STAT4 and Treg are closely related, which may be due to STAT4 transcribing related genes that affect immunity. STAT4 expression was positively correlated with the proportion of abnormal cells and promoted AML recurrence as verified by AML clinical patient samples. In addition, silencing of STAT4 significantly slowed down the proliferation capacity of HL60 cells. In conclusion, these findings suggest that STAT4 may be a potential biomarker for AML prognosis. As a key gene affecting the prognosis of AML patients, STAT4 has the potential to be a candidate diagnostic and prognostic biomarker for AML.

A red fluorescent carbon dots with good water solubility for rapid detection of Al3+ in actual samples.

We developed a facile strategy for the fabrication of red fluorescent carbon nanodots (R-CDs) and demonstrated their applications for Al3+ sensing. Red-emission carbon dots (CDs) were synthesized using a simple hydrothermal treatment with citric acid and urea as precursors, manifesting intriguing red-emission behaviour at 610 nm. With increasing Al3+ concentration, the fluorescence band at 610 nm decreased gradually. Monitoring the intrinsic fluorescence variation (I610nm ), as-prepared CDs were developed as an effective platform for fluorescent Al3+ sensing, with a linear range of 0.5-60.0 µM and a detection limit of 3.0 nM. More importantly, R-CDs have been applied successfully to the analysis of Al3+ in actual samples with satisfactory recoveries in the range 97.12-102.05%, which indicated that obtained CDs could be implemented as an effective tool for the identification and detection of Al3+ in actual samples.

The role of the thalamus in modular functional networks in temporal lobe epilepsy with cognitive impairment.

OBJECTIVE: Cognitive deficit is common in patients with temporal lobe epilepsy (TLE). Here, we aimed to investigate the modular architecture of functional networks associated with distinct cognitive states in TLE patients together with the role of the thalamus in modular networks. METHODS: Resting-state functional magnetic resonance imaging scans were acquired from 53 TLE patients and 37 matched healthy controls. All patients received the Montreal Cognitive Assessment test and accordingly were divided into TLE patients with normal cognition (TLE-CN, n = 35) and TLE patients with cognitive impairment (TLE-CI, n = 18) groups. The modular properties of functional networks were calculated and compared including global modularity Q, modular segregation index, intramodular connections, and intermodular connections. Thalamic subdivisions corresponding to the modular networks were generated by applying a 'winner-take-all' strategy before analyzing the modular properties (participation coefficient and within-module degree z-score) of each thalamic subdivision to assess the contribution of the thalamus to modular functional networks. Relationships between network properties and cognitive performance were then further explored. RESULTS: Both TLE-CN and TLE-CI patients showed lower global modularity, as well as lower modular segregation index values for the ventral attention network and the default mode network. However, different patterns of intramodular and intermodular connections existed for different cognitive states. In addition, both TLE-CN and TLE-CI patients exhibited anomalous modular properties of functional thalamic subdivisions, with TLE-CI patients presenting a broader range of abnormalities. Cognitive performance in TLE-CI patients was not related to the modular properties of functional network but rather to the modular properties of functional thalamic subdivisions. CONCLUSIONS: The thalamus plays a prominent role in modular networks and potentially represents a key neural mechanism underlying cognitive impairment in TLE.

Supramolecular polymers with dual energy storage mechanism for high-performance supercapacitors.

In this paper, we prepared the supramolecular polymers (MWCNT-APP-s) with a dual energy storage mechanism as the electrode materials by the coordination of four transition metal ions with the small molecule chelator (APP) and functionalized carbon nanotubes, respectively. Among four MWCNT-APP-s, MWCNT-APP-Fe has the characteristics of moderate micropore/mesopore, significant hydrophobicity, redox property and functional groups. Interestingly, the redox reaction of Fe3+/Fe2+ and -CN-/-CN- transformation give MWCNT-APP-Fe an energy storage basis of pseudocapacitance, while MWCNTs and the micro/mesopore structure in MWCNT-APP-Fe provide a double-layer energy storage platform. As expected, on base of the dual energy storage mechanism, the symmetric supercapacitor assembled with MWCNT-APP-Fe has a higher specific capacity (Cs, 421 F g-1 at 1 mV s-1) as well as a long-lasting stability of 94.8% capacity retention with 99% Coulombic efficiency after 10,000 cycles at 20 mV s-1. More notably, the relevant aqueous Zn2+ hybrid supercapacitor provides a high capacity (Cm) of 191 mAh g-1 at 0.5 A g-1 and a long duration of over 2000 cycles at 50 A g-1, with a capacity retention of 92.4%. In summary, MWCNT-APP-Fe with a dual energy storage mechanism enables a potential application as an electrode material for high-performance supercapacitor.

A shock flash breaking out of a dusty red supergiant.

Shock-breakout emission is light that arises when a shockwave, generated by the core-collapse explosion of a massive star, passes through its outer envelope. Hitherto, the earliest detection of such a signal was at several hours after the explosion1, although a few others had been reported2-7. The temporal evolution of early light curves should provide insights into the shock propagation, including explosion asymmetry and environment in the vicinity, but this has been hampered by the lack of multiwavelength observations. Here we report the instant multiband observations of a type II supernova (SN 2023ixf) in the galaxy M101 (at a distance of 6.85 ± 0.15 Mpc; ref. 8), beginning at about 1.4 h after the explosion. The exploding star was a red supergiant with a radius of about 440 solar radii. The light curves evolved rapidly, on timescales of 1-2 h, and appeared unusually fainter and redder than predicted by the models9-11 within the first few hours, which we attribute to an optically thick dust shell before it was disrupted by the shockwave. We infer that the breakout and perhaps the distribution of the surrounding dust were not spherically symmetric.

Thermal comfort and adaptive behaviors in office buildings: A pilot study in Turpan (China) during summer.

Nowadays, evaporatively cooled office buildings commonly observed in dry hot areas in summer of China. However, few dedicated studies to record the local residents' thermal comfort and adaptability in these buildings. The contribution of adaptive comfort theory on thermal perception still remains unclear for optimizing office building design parameters. Hence, to deeper probe the adaptive thermal comfort of the related indoor environment, a field study of office buildings during summer considering evaporative cooling air conditioned (ECA) and naturally ventilated (NV) mode was conducted in Turpan, China. Based on 931 valid datasets collected from questionnaires, we found that the neutral temperature (Tn) of 28.4 °C in ECA group, 0.6 °C lower than NV group (29.0 °C). A lower air temperature (Ta) and higher humidity (RH)/air-velocity (Va) were expected in two modes, and Va has a stronger influence than RH on mean thermal sensation votes (MTSV). Meanwhile, occupants can adapt to current indoor environment through physiological, psychological and behavioral adjustments, while the clothing regulation had limited effect on MTSV unless the outdoor temperature exceeds 38 °C. Whether in ECA or NV mode, the predicted mean votes (PMV) model overestimated actual thermal sensation when operative temperature (Top) beyond 28 °C. Adaptive models were also proved varied from that in current standards, which indicated that they were not suitable for evaluating the studied buildings in Turpan. Above findings could suggest us a better understanding of the occupants' thermal adaptability, thereby providing the reference of design parameters revision and passive strategies for local newly/renovated buildings.

FGF21 alleviates adipose stem cell senescence via CD90 glycosylation-dependent glucose influx in remodeling healthy white adipose tissue.

The senescence of adipose stem cells (ASCs) impairs healthy adipose tissue remodeling, causing metabolic maladaptation to energy surplus. The intrinsic molecular pathways and potential therapy targets for ASC senescence are largely unclear. Here, we showed that visceral ASCs were prone to senescence that was caused by reactive oxygen species (ROS) overload, especially mitochondrial ROS. These senescent ASCs failed to sustain efficient glucose influx, pentose phosphate pathway (PPP) and redox homeostasis. We showed that CD90 silence restricted the glucose uptake by ASCs and thus disrupted their PPP and anti-oxidant system, resulting in ASC senescence. Notably, fibroblast growth factor 21 (FGF21) treatment significantly reduced the senescent phenotypes of ASCs by augmenting CD90 protein via glycosylation, which promoted glucose influx via the AKT-GLUT4 axis and therefore mitigated ROS overload. For diet-induced obese mice, chronic administration of low-dose FGF21 relieved their visceral white adipose tissue (VAT) dysfunction and systemic metabolic disorders. In particular, VAT homeostasis was restored in FGF21-treated obese mice, where ASC repertoire was markedly recovered, accompanied by CD90 elevation and anti-senescent phenotypes in these ASCs. Collectively, we reveal a molecular mechanism of ASC senescence by which CD90 downregulation interferes glucose influx into PPP and redox homeostasis. And we propose a FGF21-based strategy for healthy VAT remodeling, which targets CD90 glycosylation to correct ASC senescence and therefore combat obesity-related metabolic dysfunction.

Hepatocyte TIPE2 is a fasting-induced Raf-1 inactivator that drives hepatic gluconeogenesis to maintain glucose homeostasis.

BACKGROUND: The liver regulates metabolic balance during fasting-feeding cycle. Hepatic adaptation to fasting is precisely modulated on multiple levels. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a negative regulator of immunity that reduces several liver pathologies, but its physiological roles in hepatic metabolism are largely unknown. METHODS: TIPE2 expression was examined in mouse liver during fasting-feeding cycle. TIPE2-knockout mice, liver-specific TIPE2-knockout mice, liver-specific TIPE2-overexpressed mice were examined for fasting blood glucose and pyruvate tolerance test. Primary hepatocytes or liver tissues from these mice were evaluated for glucose production, lipid accumulation, gene expression and regulatory pathways. TIPE2 interaction with Raf-1 and TIPE2 transcription regulated by PPAR-α were examined using gene overexpression or knockdown, co-immunoprecipitation, western blot, luciferase reporter assay and DNA-protein binding assay. RESULTS: TIPE2 expression was upregulated in fasted mouse liver and starved hepatocytes, which was positively correlated with gluconeogenic genes. Liver-specific TIPE2 deficiency impaired blood glucose homeostasis and gluconeogenic capacity in mice upon fasting, while liver-specific TIPE2 overexpression elevated fasting blood glucose and hepatic gluconeogenesis in mice. In primary hepatocytes upon starvation, TIPE2 interacted with Raf-1 to accelerate its ubiquitination and degradation, resulting in ERK deactivation and FOXO1 maintenance to sustain gluconeogenesis. During prolonged fasting, hepatic TIPE2 deficiency caused aberrant activation of ERK-mTORC1 axis that increased hepatic lipid accumulation via lipogenesis. In hepatocytes upon starvation, PPAR-α bound with TIPE2 promoter and triggered its transcriptional expression. CONCLUSIONS: Hepatocyte TIPE2 is a PPAR-α-induced Raf-1 inactivator that sustains hepatic gluconeogenesis and prevents excessive hepatic lipid accumulation, playing beneficial roles in hepatocyte adaptation to fasting.

Anisotropic and Highly Sensitive Flexible Strain Sensors Based on Carbon Nanotubes and Iron Nanowires for Human-Computer Interaction Systems.

Flexible strain sensors for multi-directional strain detection are crucial in complicated hman-computer interaction (HCI) applications. However, enhancing the anisotropy and sensitivity of the sensors for multi-directional detection in a simple and effective method remains a significant issue. Therefore, this study proposes a flexible strain sensor with anisotropy and high sensitivity based on a high-aspect-ratio V-groove array and a hybrid conductive network of iron nanowires and carbon nanotubes (Fe NWs/CNTs). The sensor exhibits significant anisotropy, with a difference in strain detection sensitivity of up to 35.92 times between two mutually perpendicular directions. Furthermore, the dynamic performance of the sensor shows a good response rate, ranging from 223 ms to 333 ms. The sensor maintains stability and consistent performance even after undergoing 1000 testing cycles. Additionally, the constructed flexible strain sensor is tested using the remote control application of a trolley, demonstrating its high potential for usage in practical HCI systems. This research offers a significant competitive advantage in the development of flexible strain sensors in the field of HCI.

The role of redox-mediated lysosomal dysfunction and therapeutic strategies.

Redox homeostasis refers to the dynamic equilibrium between oxidant and reducing agent in the body which plays a crucial role in maintaining normal physiological activities of the body. The imbalance of redox homeostasis can lead to the development of various human diseases. Lysosomes regulate the degradation of cellular proteins and play an important role in influencing cell function and fate, and lysosomal dysfunction is closely associated with the development of various diseases. In addition, several studies have shown that redox homeostasis plays a direct or indirect role in regulating lysosomes. Therefore, this paper systematically reviews the role and mechanisms of redox homeostasis in the regulation of lysosomal function. Therapeutic strategies based on the regulation of redox exerted to disrupt or restore lysosomal function are further discussed. Uncovering the role of redox in the regulation of lysosomes helps to point new directions for the treatment of many human diseases.

Dl-3-n-butylphthalide exerts neuroprotective effects by modulating hypoxia-inducible factor 1-alpha ubiquitination to attenuate oxidative stress-induced apoptosis.

Dl-3-n-butylphthalide is used to treat mild and moderate acute ischemic stroke. However, the precise underlying mechanism requires further investigation. In this study, we investigated the molecular mechanism of Dl-3-n-butylphthalide action by various means. We used hydrogen peroxide to induce injury to PC12 cells and RAW264.7 cells to mimic neuronal oxidative stress injury in stroke in vitro and examined the effects of Dl-3-n-butylphthalide. We found that Dl-3-n-butylphthalide pretreatment markedly inhibited the reduction in viability and reactive oxygen species production in PC12 cells caused by hydrogen peroxide and inhibited cell apoptosis. Furthermore, Dl-3-n-butylphthalide pretreatment inhibited the expression of the pro-apoptotic genes Bax and Bnip3. Dl-3-n-butylphthalide also promoted ubiquitination and degradation of hypoxia inducible factor 1α, the key transcription factor that regulates Bax and Bnip3 genes. These findings suggest that Dl-3-n-butylphthalide exhibits a neuroprotective effect on stroke by promoting hypoxia inducible factor-1α ubiquitination and degradation and inhibiting cell apoptosis.

GIPC2 is a tumor suppressor gene for acute myeloid leukemia and induces apoptosis of leukemia cells by regulating the PI3K/AKT pathway.

Aims: To explore the expression and methylation levels of GIPC2 in acute myeloid leukemia (AML), discuss the mechanism of GIPC2 in AML and provide new strategies for the diagnosis and treatment of AML. Methods: qPCR, western blotting, cell counting kit-8 assay, bisulfite sequencing and other experiments were used in this study. Results: The expression of GIPC2 was found to be downregulated in AML and is mainly affected by DNA promoter methylation. Decitabine can demethylate the promoter region of GIPC2, and GIPC2 expression is upregulated after demethylation. Overexpression of GIPC2 in HL-60 cells can induce apoptosis by inhibiting the PI3K/AKT pathway. Conclusion: Our findings identify that GIPC2 is associated with the PI3K/AKT signaling pathway and may represent a potential therapeutic target and biomarker for the management of AML.

Multi-trait analysis reveals large interspecific differences for phytoplankton in response to thermal change.

Understanding the responses of multiple traits in phytoplankton, and identifying interspecific variabilities to thermal changes is crucial for predicting the impacts of ocean warming on phytoplankton distributions and community structures in future scenarios. Here, we applied a trait-based approach by examining the patterns in multi-traits variations (eight traits) and interspecific variabilities in five phytoplankton species (two diatoms, three dinoflagellates) in response to a wide range of ecologically relevant temperatures (14-30 °C). Our results show large inter-traits and interspecific variabilities of thermal reaction norms in all of the tested traits. We also found that the interspecific variability exceeded the variations induced by thermal changes. Constrained variations and trade-offs between traits both revealed substantial interspecific differences and shifted as the temperature changed. Our study helps to understand the species-specific response patterns of multiple traits to ocean warming and to investigate the implications of these responses in the context of global change.

Identification of PPT1 as a lysosomal core gene with prognostic value in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent cancer worldwide with a poor prognosis. Unfortunately, there are few reports on effective biomarkers for HCC, identification of novel cancer targets is urgently needed. Lysosomes are central organelles for degradation and recycling processes in cells, and how lysosome-related genes are involved in the progression of hepatocellular carcinoma remains unclear. The aim of the present study was to identify key lysosome-related genes affecting HCC. In the present study, lysosome-related genes involved in HCC progression were screened based on the TCGA (The Cancer Genome Atlas) dataset. Differentially expressed genes (DEGs) were screened, and core lysosomal genes were obtained in combination with prognostic analysis and protein interaction networks. Two genes were associated with survival, and their prognostic value was validated by prognostic profiling. After mRNA expression validation and IHC, the palmitoyl protein thioesterase 1 (PPT1) gene was identified as an important lysosomal-related gene. We demonstrated that PPT1 promotes the proliferation of HCC cells in vitro. In addition, quantitative proteomics and bioinformatics analysis confirmed that PPT1 acts by affecting the metabolism, localization, and function of various macromolecular proteins. The present study reveals that PPT1 could be a promising therapeutic target for the treatment of HCC. These findings provided new insights into HCC and identified candidate gene prognosis signatures for HCC.

CX3CR1hi macrophages sustain metabolic adaptation by relieving adipose-derived stem cell senescence in visceral adipose tissue.

Adipose-derived stem cells (ASCs) drive healthy visceral adipose tissue (VAT) expansion via adipocyte hyperplasia. Obesity induces ASC senescence that causes VAT dysfunction and metabolic disorders. It is challenging to restrain this process by biological intervention, as mechanisms of controlling VAT ASC senescence remain unclear. We demonstrate that a population of CX3CR1hi macrophages is maintained in mouse VAT during short-term energy surplus, which sustains ASCs by restraining their senescence, driving adaptive VAT expansion and metabolic health. Long-term overnutrition induces diminishment of CX3CR1hi macrophages in mouse VAT accompanied by ASC senescence and exhaustion, while transferring CX3CR1hi macrophages restores ASC reservoir and triggers VAT beiging to alleviate the metabolic maladaptation. Mechanistically, visceral ASCs attract macrophages via MCP-1 and shape their CX3CR1hi phenotype via exosomes; these macrophages relieve ASC senescence by promoting the arginase1-eIF5A hypusination axis. These findings identify VAT CX3CR1hi macrophages as ASC supporters and unravel their therapeutic potential for metabolic maladaptation to obesity.

DNA methylation and gene transcription act cooperatively in driving the adaptation of a marine diatom to global change.

Genetic changes together with epigenetic modifications such as DNA methylation have been demonstrated to regulate many biological processes and thereby govern the response of organisms to environmental changes. However, how DNA methylation might act cooperatively with gene transcription and thereby mediate the long-term adaptive responses of marine microalgae to global change is virtually unknown. Here we performed a transcriptomic analysis, and a whole-genome bisulfite sequencing, along with phenotypic analysis of a model marine diatom Phaeodactylum tricornutum adapted for 2 years to high CO2 and/or warming conditions. Our results show that the methylated islands (peaks of methylation) mCHH were positively correlated with expression of genes in the subregion of the gene body when the populations were grown under high CO2 or its combination with warming for ~2 years. We further identified the differentially expressed genes (DEGs), and hence the metabolic pathways in which they function, at the transcriptomics level in differentially methylated regions (DMRs). Although DEGs in DMRs contributed only 18-24% of the total DEGs, we found that those DEGs acted cooperatively with DNA methylation and then regulated key processes such as central carbon metabolism, amino acid metabolism, ribosome biogenesis, terpenoid backbone biosynthesis, and degradation of misfolded proteins. Taken together, by integrating transcriptomic, epigenetic, and phenotypic analysis, our study provides evidence for DNA methylation acting cooperatively with gene transcription to contribute to the adaptation of microalgae to global changes.

Long-term adaptation to elevated temperature but not CO2 alleviates the negative effects of ultraviolet-B radiation in a marine diatom.

Multifaceted changes in marine environments as a result of anthropogenic activities are likely to have a compounding impact on the physiology of marine phytoplankton. Most studies on the combined effects of rising pCO2, sea surface temperature, and UVB radiation on marine phytoplankton were only conducted in the short-term, which does not allow to test the adaptive capacity of phytoplankton and associated potential trade-offs. Here, we investigated populations of the diatom Phaeodactylum tricornutum that were long-term (∼3.5 years, ∼3000 generations) adapted to elevated CO2 and/or elevated temperatures, and their physiological responses to short-term (∼2 weeks) exposure of two levels of ultraviolet-B (UVB) radiation. Our results showed that while elevated UVB radiation showed predominantly negative effects on the physiological performance of P. tricornutum regardless of adaptation regimes. Elevated temperature alleviated these effects on most of the measured physiological parameters (e.g., photosynthesis). We also found that elevated CO2 can modulate these antagonistic interactions, and conclude that long-term adaptation to sea surface warming and rising CO2 may alter this diatom's sensitivity to elevated UVB radiation in the environment. Our study provides new insights into marine phytoplankton's long-term responses to the interplay of multiple environmental changes driven by climate change.